A phase III multi-center, randomized, open-label study to evaluate the efficacy and safety of Lutathera in combination with best supportive care octreotide long-acting (30 mg), when given as a 1st line treatment in GEP-NET patients with high proliferation rate tumors (G2 and G3), in comparison to treatment with high dose (60 mg) octreotide long-acting.

Phase 1

Conditions: Patients with somatostatin receptor positive, well-differentiated G2 and G3, advanced GEP NETs
MedDRA version: 21.0Level: PTClassification code 10052399Term: Neuroendocrine tumourSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10077559Term: Gastroenteropancreatic neuroendocrine tumour diseaseSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10077560Term: Gastroenteropancreatic neuroendocrine tumor diseaseSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2019-001562-15-ES

Lead Sponsor: Advanced Accelerator Applications SA

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 222

Inclusion Criteria

1. Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
2. Ki67 index =10 and = 55%.
3. Patients =15 years of age and a body weight of >40 kg at screening.
4. Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT imaging or [68Ga]-DOTA-TATE PET/CT imaging (e.g. NETSPOT®) or Somatostatin Receptor scintigraphy (SRS) with 111In-pentetreotide (Octreoscan® SPECT/CT).
5. The tumor uptake observed in the target lesions must be > normal liver uptake observed on planar imaging.
6. Karnofsky Performance Score (KPS) =60.
7. Presence of at least 1 measurable site of disease.
8. Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
Are the trial subjects under 18? yes
Number of subjects for this age range: 10
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 112

Exclusion Criteria

1. Creatinine clearance <40 mL/min calculated by the Cockroft Gault method.
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x10^9/L (2000/mm^3); platelets <75x10^9/L (75x10^3/mm^3).
3. Total bilirubin >3 x ULN.
4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy or lactation.
6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 6 months after study drug discontinuation.
7. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
8. Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization.
9. Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics.
10. Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies administered for more than 1 month and within 12 weeks prior to randomization in the study.
11. Any previous radioembolization, chemoembolization and radiofrequency ablation.
12. Any surgery within 12 weeks prior to randomization in the study.
13. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
14. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization, preferably via gated equilibrium radionuclide ventriculography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient’s measured cardiac ejection fraction in these patients must be >40% before randomization.
15. QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.
16. Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.
17. Hyperkaleamia >6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment.
18. Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (eg octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera, unless the tumor uptake on target lesions observed by study-permitted somatostatin receptor imaging (SRI) modalities during continued long-acting SSA treatment is greater than the liver uptake observed by planar imaging.
19. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
20. Prior external beam radiation therapy to more than 25% of the bone marrow.
21. Current spontaneous urinary incontinence.
22. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To demonstrate that Lutathera is superior to active comparator in delaying the time-to-first occurrence of progression or death (PFS) as first line treatment.;Secondary Objective: Key secondary objectives:<br>-To demonstrate the superiority of Lutathera, compared to active comparator, in terms of objective response <br>-To demonstrate the superiority of Lutathera, compared to active comparator, in terms of time to deterioration in selected QoL items/scales.<br><br>Other Secondary Objectives:<br>-To evaluate the efficacy of Lutathera, compared to active comparator, in keeping the disease under control<br>-To evaluate the efficacy of Lutathera, compared to active comparator, in terms of duration of response<br>-To evaluate the safety and tolerability of Lutathera<br>-To evaluate the effect of Lutathera on survival;Primary end point(s): Progression Free Survival (PFS): Time from randomization to the first line progression;Timepoint(s) of evaluation of this end point: After 99 PFS events

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): -ORR: rate of complete and partial responses (CR, PR)<br><br>-Time to decline (TTD) by 10 points from baseline in<br>the total score for health status as measured by the<br>EORTC QLQ-G.I.NET21 questionnaire, EORTC QLQC30 questionnaire: global health status (TTD)-diarrhea (TTD)-fatigue, (TTD)- pain (TTD).;Timepoint(s) of evaluation of this end point: At the end of treatment phase or after discontinuation

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